Transcription Regulation and Cell Signaling Control

of Normal Lymphocyte Development and Lymphoid Malignancies

Molecular pathogenesis of lymphomas situates at the crossroad of lymphocyte development, and cancer genetics, and involves all aspects of tumor-host interactions. Thus, we constantly draw upon the most recent advances in these fields to address mechanism questions that are related to lymphoma initiation, development, and therapeutic response. As each lymphoma entity often relates to a specific B/T cell activation/differentiation state that is phenotypically “frozen” by the malignant transformation process, our research also provides valuable insights to the regulatory processes that govern the normal immune system. Our studies have three major goals: to better understand B and T cell development in molecular terms, to decipher how this process is perturbed during lymphomagenesis, and to develop mechanism-based novel therapies to improve patient outcome.

The germinal center (GC) response is a particularly important stage in B cell development that is specifically evolved to support the production of high affinity antibodies and B cell memory. Dysregulated GC responses underlie the development of many types of B cell lymphomas and autoimmune diseases. GCs are dynamic and specialized structures in the secondary lymphoid organs where the B cell genome is subject to two types of genetic alterations catalyzed by AID (activation induced cytidine deaminase), e.g. Ig class switch recombination and somatic hypermutation. Mutated B cells undergo positive and negative selections through interactions with follicular dendritic cells, follicular T helper (Tfh) and T follicular regulatory (Tfr) cells. Only the fittest B cells are licensed to terminally differentiate into memory or plasma cells. At the single cell level, the acquisition and termination of GC phenotype is a coordinated response to various extracellular and intracellular stimuli; yet the precise sequence and nature of these stimuli are incompletely understood.

Our previous studies have revealed important mechanisms that govern the expression and activity of BCL6, the master regulator of GC response, and demonstrated functional interactions between BCL6 and several cell signaling pathways including RhoA, NF-kB, and Jak/STAT3. In the context of diffuse large B-cell lymphomas (DLBCL), another focus of our investigation was on the IL-6/Jak/STAT3 signaling pathway. We have characterized expression regulation of STAT3, cause and consequences of its aberrant activity in DLBCL development and therapeutic response. The functional contribution of this pathway to normal plasma cell maturation was also investigated. 

 Since 2016, the major focus of our research program has switched to adult T-cell leukemia/lymphoma (ATLL), a disease of malignant CD4+ T cells that develops in 4-5% of individuals infected with the human T-cell lymphotropic virus 1 (HTLV-1). The medium survival of ATLL patients diagnosed in North America is only about 7 months, pointing to an urgent unmet need in the therapeutic space. Mainly because of the Bronx’s immigrant makeup, the Montefiore Medical Center treats a sizable fraction of all ATLL cases in the U.S., and thus we have unique access to ATLL patient samples and unmatched opportunities to perform preclinical and clinical studies. We recently reported that ATLL patients diagnosed in North American (NA-ATLL) have a distinct genomic landscape compared to the Japanese cohort (J-ATLL). Specifically, NA-ATLL is characterized by a much higher frequency of prognostic epigenetic mutations and is targetable preclinically with DNA de-methylation drugs. Ongoing studies in our laboratory support the concept that NA- and J-ATLL share similarities in clinical behavior and pathogenesis but also have clear distinctions in mutation pattern, cell cycle regulation, immunophenotype, and response to experimental therapeutics. Since host anti-HTLV-1/anti-ATLL immune response plays a key role in ATLL development, we have also begun to examine how host immunity, in particular CD8⁺ cytotoxic response, is impacted during ATLL development. Our preliminary findings support the concept that for an ATLL treatment to be most effective, ATLL-induced immunosuppression must be overcome along with recruitment restoration of anti-ATLL CD8⁺ T cell effector and memory responses. Looking forward, insights uncovered from our ongoing projects are expected to pave the way for novel pathway-targeted and immune-modulatory therapies for ATLL patients and possibly other types of T-cell malignancies.

We are currently pursuing the following research questions:

1. How does BCL6 contribute to the pathogenesis and cell identity of NA-ATLL?

2. What is the genetic and clonal evolution basis that may contribute to the differences between NA- and J-ATLL?

3. How do the ATLL cells suppress the function of normal T cells to achieve immune escape? 

Selected Publications Since 2013

Madugula, K., Demarino, C., Ginwala, R., Teixeira, V., Joseph, J., Khan, Z.K.,  Sales, D.,  Kashanchi, F., Rushing, A.W.,  Lemasson, I., Harhaj, E.W.,  Janakiram, M., Ye, B.H.,  and Jain, P. Regulation of HTLV-1 3'LTR antisense promoter by Myocyte Enhancer Factor-2C in the context of Ault T-cell leukemia and lymphoma. Haematologica. 2022 107(12):2928-2943. doi: 10.3324/haematol.2021.279542.

Kogure, Y., Kameda, T., Koya1, J., Yoshimitsu, M., Nosaka, K., Yasunaga, J-I., Imaizumi, Y., Watanabe, M., Saito, Y., Ito, Y.,  McClure, M.B., Tabata, M.,  Shingaki, S.,  Yoshifuji, K., Chiba, K., Okada, A., Kakiuchi, N., Nannya, Y.,  Kamiunten, A., Shide, K., Hidaka, T., Kubuki, Y., Kitanaka, A., Hidaka, M.,  Utsunomiya, A., Ramos, J.C., Shibata, T., Takeuchi, K., Takaori-Kondo, A., Miyazaki, Y., Matsuoka, M., Ishitsuka, K., Shiraishi, Y., Miyano, S., Ogawa, S., Ye, B.H.*, Shimoda, K.*, and Kataoka, K.*. Whole-genome landscape of adult T-cell leukemia/lymphoma. *communication authors. Blood 2022 139(7):967-982. doi: 10.1182/blood.2021013568. PMID: 34695199

Shah, U.A., Shah, N., Qiao, B., Acuna-Villaorduna, A., Pradhan, K, Sica, A.,  Shastri, A., Mantzaris, I., Derman, O., Kornblum, N., Braunschweig, I.,  Ye, B.H., Verma, A., Janakiram, M. Epidemiology and survival trend of Adult T-cell Leukemia/Lymphoma in the United States: An Analysis of the NPCR, SEER, and NYSCR datasets.  Cancer. 2020 Feb 1;126(3):567-574. doi: 10.1002/cncr.32556. PMID: 31769871

Rauch, D.A., Conlon, K.C., Janakiram, M., Brammer, J.E., Harding, J.C., Ye, B.H., Zang, X., Ren, X., Olson, S., Cheng, X., Miljkovic, M.D., Sundaramoorth, H., Joseph, A., Griffith, M., Waldmann, T.A., and  Ratner, L. Rapid Progression of Adult T-Cell Leukemia/Lymphoma as Tumor Infiltrating Treg Cells after PD-1 Blockade. Blood. 2019. 134:1406-1414. doi: 10.1182/blood.2019002038.  PMID: 31467059

Chung EY, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, Ren X, Pradhan K, Bartholdy B, Wei X, Zou Y, Zhang J, Ogawa S, Steidl U, Zang X, Verma A, Janakiram M, Ye BH. PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma. Clin Cancer Res. 25:3589–601, 2019. PMID: 30862694 (Cover Article). [PDF Full Text]

Shah UA, Chung EY, Giricz O, Pradhan K, Kataoka K, Gordon-Mitchell S, Bhagat TD, Mai Y, Wei Y, Ishida E, Choudhary GS, Joseph A, Rice R, Gitego N, Parrish C, Bartenstein M, Goel S, Mantzaris I, Shastri A, Derman O, Binder A, Gritsman K, Kornblum N, Braunschweig I, Bhagat C, Hall J, Graber A, Ratner L, Wang Y, Ogawa S, Verma A*, Ye BH*, Janakiram M*. North American ATLL has a Distinct Mutational and Transcriptional Profile and responds to epigenetic therapies. Blood. 2018 Aug 13. pii: blood-2018-01-824607. doi: 10.1182/blood-2018-01-824607. PMID: 30104217. * communication authors. [PDF Full Text]

Mai Y, Yu JJ, Bartholdy B, Xu-Monette ZY, Knapp EE, Yuan F, Chen H, Ding BB, Yao Z, Das B, Zou Y, Young KH, Parekh S, Ye BH. Subtype-specific mechanism for Doxorubicin-triggered cytotoxicity in diffuse large B cell lymphomas. Blood. 128(24):2797-2807, 2016. PMID: 27737889. [PDF FULL Text]

Alvarez, M. J., Shen, Y., Giorgi, F.M., Lachmann, A., Ding, B.B., Ye, B.H., Califano, A. Network-based inference of protein activity helps functionalize the genetic landscape of cancer. Nature Genet, 48(8):838-4, 2016. PMID: 27322546. [PDF Full Text]

Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell. 27(3):409-25, 2015. PMID: 25759025. [PDF Full Text]

Zhao, H., Bauzon, F., Bi, E., Yu, J.J., Fu, H., Lu, Z., Cui, J., Jeon, H., Zang, X., Ye, B.H. and Zhu, L. Mutating Threonine 187 of p27 To An Alanine Prevents Pituitary Tumorigenesis By Two-Hit Loss Of Rb1 And Enhances Humoral Immunity In Old Age. J Biol Chem. 290(9):5787-809. 2015. PMID: 25583987, PMCID: PMC4342489.[PDF Full Text]

Wei, X., Xu, M., Wei, Y., Huang, F., Zhao, T., Li, X., Feng, R.*, and Ye, B.H.* The addition of rituximab to CHOP therapy altered the prognostic significance of CD44 expression. (*Communication authors). J Hematol Oncol. 7(1):34-36, 2014. PMID: 24739401, PMCID: PMC4022142. [PDF Full Text]

Huang, X., Meng, B., Iqbal, J., Ding, B.B., Perry, A.M., Cao, W., Smith, L.M., Bi, C., Jiang, C., Greiner, T.C., Weisenburger, D., Rimsza, L., Rosenwald, A., Ott, G., Delabie, J., Campo, E., Braziel, R., Gascoyne, R., Cook, J., Tubbs, R., Jaffe, E., Armitage, J., Vose, J., Staudt, L., McKeithan, T.W., Chan, W., Ye, B.H.*, Fu, K*. Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma patients treated with R-CHOP. J Clin Oncol., 31:4520-8, 2013 (*communication authors). [PDF Full Text]

Ye, B.H., Mai, Y. A Bach2 Link between Pre-B Cell Receptor Checkpoint and Pre-B Cell ALL. Cancer Cell. 2013 24(3):282-4. [PDF Full Text]

Ding, B.B., Bi, E., Chen, H., Yu, J.J. and Ye, B.H. IL-21/STAT3 and CD40L/NF-kappaB synergistically promote plasma cell differentiation through upregulation of Blimp-1. J Immunol. 190(4):1827-36, 2013. [PDF Full Text]